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Dual Therapy With Infliximab and Immunomodulator Reduces One-Year Rates of Hospitalization and Surgery Among Veterans With Inflammatory Bowel Disease
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2013;11:1281–1287
Dual Therapy With Infliximab and Immunomodulator Reduces One-Year Rates of Hospitalization and Surgery Among Veterans With Inflammatory Bowel Disease NEENA S. ABRAHAM,*,‡ PETER RICHARDSON,‡ DIANA CASTILLO,‡ and SUNANDA V. KANE§ *Section of Digestive Diseases, Division of Gastroenterology and Hepatology, and ‡Houston VA Health Services Research and Development Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, Houston, Texas; and §Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, Minnesota
BACKGROUND & AIMS: Effectiveness of early treatment with biologics and immunomodulator therapy on healthcare utilization remains poorly defined. We assessed rates of hospitalization and surgery within 1 year after initiation of infliximab and/or immunomodulator therapy in a United States cohort of patients with inflammatory bowel disease.
METHODS:
We conducted a retrospective, observational cohort study of veterans with Crohn’s disease or ulcerative colitis by using administrative data from 176 Department of Veteran Affairs facilities (October 1, 2001 through September 30, 2009). Inpatient, outpatient, and death records were linked longitudinally with prescription fill data. Each person-day of follow-up was assessed for treatment with infliximab, immunomodulators, both (dual therapy), or neither. We calculated drug exposure time and used Poisson and logistic regression analyses to assess outcomes.
RESULTS:
The cohort of 20,474 patients included 8042 patients with Crohn’s disease and 12,432 with ulcerative colitis (93.9% male; 72.5% white; mean age, 60.9 – 14.5 years) prescribed infliximab (0.17%), immunomodulator (1.3%), or dual therapy (1.5%). Adjusted models revealed 50% relative reductions in hospitalization among patients who received 9.2 months of immunomodulator monotherapy, 8 months of infliximab, or 7.7 months of dual therapy. A 50% relative reduction in surgery was observed among patients receiving 7 months of infliximab or 5 months of dual therapy. Analysis of dose-response data revealed 73.1% and 92% reductions in risk of hospitalization and surgery, respectively, after 9 months of dual therapy.
CONCLUSIONS:
On the basis of a retrospective cohort study, dual therapy with infliximab and an immunomodulator for <8 months is associated with significant reductions in hospitalization and surgery within 1 year of the start of therapy. These findings indicate that patients with IBD are more likely to benefit if dual therapy is initiated earlier in their first year of therapy.
Keywords: Remicade; Imuran; Anti-Tumor Necrosis Factor (TNF)-a; Patient Management; Therapeutic Strategy.
B
iological therapies are effective in the treatment of active inflammation associated with Crohn’s disease (CD) (infliximab, adalimumab, certolizumab pegol) and ulcerative colitis (UC) (infliximab, adalimumab).1–9 Infliximab has the most extensive published clinical trial data and clinical experience. Its use is a therapeutic recommendation for moderately to severely active CD in the guidelines of the American College of Gastroenterology,10 American Gastroenterological Association,11 and the European Crohn’s and Colitis Organization12 and for moderately to severely active UC in the guidelines of the American College of Gastroenterology.13 Infliximab improves remission rates and quality of life, while reducing rates of surgery and hospitalization.14 Maintenance with infliximab was superior to placebo at week 54 (remission 14% on placebo, 28% at 5 mg/kg, 38% at 10 mg/kg; P < .05).3 Patients on scheduled maintenance therapy had greater mucosal healing,6 fewer hospitalizations and surgery,15 and improved quality of life.16 Among a subset of patients, mucosal
healing supported a sustained clinical remission leading to reduced need for surgery.6,17,18 Meta-analysis confirms that biological therapies targeting tumor necrosis factor (TNF)-a, such as infliximab, are superior to placebo in inducing remission of luminal CD (relative risk [RR], 0.87; 0.80–0.94), with a number needed to treat of eight,19 and of UC (RR, 0.72; 0.57–0.91), with a number needed to treat of four.19 Despite their clear therapeutic benefit, <15% of patients with inflammatory bowel disease (IBD) receive anti-TNF Abbreviations used in this paper: CD, Crohn’s disease; CI, confidence interval; IBD, inflammatory bowel disease; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; NSAID, nonsteroidal anti-inflammatory drug; RR, relative risk; TNF, tumor necrosis factor; UC, ulcerative colitis; VA, Veterans Affairs. © 2013 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2013.06.004
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monotherapy,14 and 40% of patients with active CD receive antiTNF agents in combination with immunomodulator agents (thiopurines or methotrexate).20 It is not known how long immunomodulator monotherapy, biologic monotherapy, or combination therapy must be used to impact hospitalization and surgical rates. Our aim was to ascertain clinical effectiveness, defined as 1-year hospitalization and IBD-related surgical rates, in a national cohort of IBD patients (CD and UC) associated with 3 strategies: (1) immunomodulator monotherapy, (2) anti–TNF-a biologic monotherapy (ie, infliximab), and (3) immunomodulator and anti–TNF-a dual therapy. We hypothesized that infliximab (monotherapy or dual therapy) would result in greater reduction in hospitalization and IBD-related surgery than the other strategies of interest.
Methods Study Design and Data Sources We conducted a retrospective, observational, cohort study of veterans (October 1, 2001–September 30, 2009) by using administrative data from 176 Department of Veteran Affairs (VA) facilities in the United States. The Baylor College of Medicine Institutional Review Board, Houston, TX, approved the research protocol. Patient prescriptions were identified from DSS National Data Extracts accessed from the Austin Automation Center, providing key prescription fill data elements, including facility, dates of fill, days’ supply, and total quantity of drug dispensed. VA administrative data were obtained from the National Patient Care Database, including the Patient Treatment File and the Outpatient Clinic File. The Patient Treatment File record contains patient demographic and hospital discharge information by using procedure codes (Current Procedural Technology and International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] diagnostic codes). The Outpatient Clinic File contains ambulatory patient demographic data, Current Procedural Technology codes, and ICD-9-CM codes. The VA Vital Status File captures deaths reported by the Beneficiary Identification and Record Locator Subsystem, Medicare Vital Status file, and the Social Security Administration. Standard algorithms were used to link administrative to pharmacy fill data to create a longitudinal inpatient, outpatient, and pharmacy refill record for each veteran in the cohort as previously published.21,22
Study Population Veterans aged 18–99 years with IBD were identified by ICD-9-CM codes by using a previously validated algorithm23 with an 88% positive predictive value, 92% sensitivity, and 99% specificity for identification of veterans with CD and an 82% positive predictive value, 84% sensitivity, and 99% specificity for
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identification of veterans with UC. Eligibility criteria included prior inpatient or outpatient VA encounter in the 365 days preceding index diagnosis (to ensure continuous VA enrollment) and no evidence of death 10 days after index prescription of a strategy of interest. Patients were assigned to the CD subcohort if ICD-9-CM codes 550.0–555.9 occurred in the absence of codes for UC (ICD-D-CM codes 556–556.9). Patients not fitting the diagnostic algorithm were excluded from analysis, as were patients with both code categories (defined as indeterminate) to decrease zero cells and improve statistical significance.
Prescription Exposure Each person-day of each cohort member’s longitudinal record was assessed for anti–TNF-a monotherapy (ie, infliximab), immunomodulator monotherapy (ie, azathioprine, mercaptopurine, or methotrexate), overlapping anti–TNF-a and immunomodulator therapy (ie, dual therapy), or absence of therapy (none), as depicted in Figure 1. Dual therapy required a minimum of 7 days of overlapping prescription fill data. Prescription fill data were assessed on a day-by-day basis, whereby an individual exposure period started at t0 and ended with termination of days’ supply or 60-day gaps in fill dates, by using our previously described methodology.21 Exposure to all IBD treatment strategies of interest and other pharmacologic risk factors was considered in a time-varying pattern, assessed daily from pharmacy fill records for each cohort member. Thus, a unique record was created for each time interval for each distinct pattern of prescription fill data per patient. For each strategy prescribed, the aggregate time spent on that regimen by each cohort member in the 365 days after index IBD diagnosis was calculated and expressed in months.
Outcomes of Interest, Potential Risk Factors, and Confounding Variables The outcomes of interest were 1-year hospitalization and 1-year IBD-associated surgical rates. Potential confounding variables considered included demographic features, Charlson–Deyo comorbidity index, and smoking status. Potential modifiers of risk measured included prior IBD-related surgeries and concomitant use of steroids; mesalamine products; nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin; cyclosporine; antibiotics; and oral contraceptives. To address prescription channeling, a propensity score24 was calculated to estimate conditional probability of receipt of each drug regimen. Propensities were analyzed as multinomial conditional probability values24 derived from a polytomous logistic regression model of predictor variables,25 chosen by biological and clinical plausibility and statistical significance (P < .1). This analysis identified potential prescription
Figure 1. Prescription exposure.
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channeling for anti–TNF-a associated with pre-IBD diagnosis prescription of fluoroquinolone antibiotics, steroid use, and immunomodulator therapy and IBD diagnosis (CD vs UC) (data not shown), and this propensity score was included in multivariable models. To adjust for bias when estimating treatment effects,26 we examined the outcome model with and without the propensity score and assessed for significance on each outcome of interest. Models for hospitalization and surgery rates did not differ significantly with inclusion of the propensity for anti–TNF-a; thus, we omitted the propensity score from final models. We also examined for potential interaction between dichotomous predictor variables and their effect on outcomes.
Analytic Methods The c2 test and analysis of variance tested for differences in demographic and clinical characteristics among subgroups. Counts of hospitalizations were modeled by Poisson regression with the drug therapy duration variables as predictors, 1 for each drug regimen of interest. To allow for nonlinearity due to varying per-duration-unit response over different drug-regimen duration ranges, duration responses were rendered as piecewise, continuous linear splines.27 Testing for interactions showed no evidence of departures from the additivity of duration responses to the 3 regimens. Surgical-event rates were modeled in a similar way, but because of low average counts, logistic regression was chosen because of its greater robustness to the effects of outliers and a large number of zero counts associated with small sample sizes of events. Model specifications
took the form: I: Y ¼ b0 þ bIMIM þ bTMTM þ bDD þ other covariates (by exposure to 3 drug therapies), where IM ¼ time on immunomodulator monotherapy, TM ¼ time on anti–TNFa monotherapy, and D ¼ time on dual therapy.
Results The cohort included 20,474 veterans (93.9% male; 72.5% white; mean age, 60.9 years [standard deviation, 14.5]), of whom 8042 had CD and 12,432 had UC (Table 1). There was an equal distribution of Charlson–Deyo comorbidity index scores of 0 vs 1. CD patients had a higher prevalence of surgery preceding 5 years before index diagnosis as well as tobacco use. UC patients were more likely to be prescribed mesalamine products (22.8%). NSAID/aspirin use was prevalent in both disease types. Steroids were prescribed in 14%, and antibiotic use was seen in 30% of subjects. Oral contraceptive use was minimal, as would be expected in a predominantly male cohort. At baseline, 65.8% of patients were on other therapies, including mesalamine monotherapy, antibiotics, steroids, antimetabolite, or cyclosporine only; 23.6% were on no therapy; and 10.6% were prescribed 1 of the prescription strategies of interest; immunomodulator monotherapy was most prevalent (82%), anti–TNF-a monotherapy was prescribed in 8.0%, and dual therapy was prescribed in 8.5%. Among patients receiving infliximab, 62.9% had evidence of induction therapy preceding a maintenance regimen. There was no meaningful difference in prevalence of induction therapy between disease types (61.9% in CD and 65.7% in UC).
Table 1. Baseline Characteristics Characteristic Baseline characteristics Average age (standard deviation) (y) <35 35–65 65 Male Race White Black Other/unknown Comorbidity Charlson–Deyo 0 Charlson–Deyo 1 Charlson–Deyo 2 Charlson–Deyo 3þ Covariate characteristics Surgery 1 y before diagnosis 5 y before diagnosis Tobacco use 1 y before diagnosis 5 y before diagnosis Antimetabolite Steroids Mesalamine NSAIDs Cyclosporine Antibiotics Oral contraceptives
All (N ¼ 20,474)
CD (n ¼ 8,042)
UC (n ¼ 12,432)
P value
60.9 1237 10,932 8305 19,230
58.8 636 4572 2834 7452
62.2 601 6360 5471 11,778
(14.1) (4.83%) (51.16%) (44.01%) (94.74%)
<.0001 <.0001 <.0001 <.0001 <.0001
(14.5) (6.04%) (53.39%) (40.56%) (93.92%)
(14.9) (7.91%) (56.85%) (35.24%) (92.66%)
14,846 (72.51%) 1955 (9.55%) 3673 (17.9%)
5900 (73.36%) 803 (9.99%) 1339 (16.7%)
8946 (71.96%) 1152 (9.27%) 2334 (18.8%)
<.0001 <.0001 <.0001
11,035 4535 2197 2707
4606 1742 814 880
6429 2793 1383 1827
<.0001 <.0001 <.0001 <.0001
(53.90%) (22.15%) (10.73%) (13.22%)
294 (1.44%) 382 (1.87%) 1836 3018 137 2875 4220 7904 42 5883 209
(8.97%) (14.74%) (0.67%) (14.04%) (20.61%) (38.61%) (0.21%) (28.73%) (1.02%)
(57.27%) (21.66%) (10.12%) (10.94%)
131 (1.63%) 172 (2.14%) 833 1313 65 1112 1386 3016 11 2327 77
(10.36%) (16.33%) (0.81%) (13.83%) (17.23%) (37.50%) (0.14%) (28.94%) (0.96%)
(51.71%) (22.47%) (11.12%) (14.70%)
163 (1.31%) 210 (1.69%) 1003 1705 72 1763 2834 4888 31 3556 132
(8.07%) (13.71%) (0.58%) (14.18%) (22.80%) (39.32%) (0.25%) (28.60%) (1.06%)
.0619 .0202 <.0001 <.0001 .0496 .4768 <.0001 .0092 .0821 .6082 .4684
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Figure 2. Hospitalization rates.
Hospitalization Rates One-year hospitalization rates are shown for each prescription strategy in Figure 2, where we demonstrate the time to result in a 50% reduction in hospitalization rate. A 50% reduction in hospitalization rate can be observed after 9.2 months of immunomodulator therapy (P < .0001), after 8 months of anti–TNF-a monotherapy (P < .0001), and with 7.7 months of dual therapy (P ¼ .02). All models were adjusted for diagnosis (UC or CD), smoking status, race/ethnicity, prescription channeling, and pharmacologic effect modifiers (steroids, mesalamine products, NSAIDs, aspirin, cyclosporine, antibiotics, and oral contraceptives). Dose response was calculated to estimate the effect of prescription strategy on hospitalization (Table 2) compared with periods of time with no drug exposure (control). The relative reduction in hospitalization improved as time spent on therapy increased. Model-based relative reduction in hospitalization Table 2. First-Year Hospitalization Rate and Surgical Risk Reductions by Drug Therapy Durations
Duration of therapy Immunomodulator monotherapy 1 month 3 months 6 months 9 months 12 months Anti–TNF-a monotherapy 1 month 3 months 6 months 9 months 12 months Dual therapy 1 month 3 months 6 months 9 months
Relative rate reduction in hospitalizations (compared with no drug exposure) (%)
RR reduction in surgery (compared with no drug exposure) (%)
4.9 13.9 25.9 36.2 45.1
3.6 10.5 20.0 28.4 35.9
1.3 3.9 37.9 67.1 82.6
0.1 0.4 44.2 90.2 98.3
0.7 2.1 4.1 86.1
24.4 56.8 81.4 92.0
rates after 9 months of immunomodulator was 36.2% (95% confidence interval [CI], 24.5%–46.2%); after 9 months of anti–TNF-a monotherapy it was 67.1% (95% CI, 45.6%–80.1%) and 86.1% (95% CI, 55.4%–95.7%) for dual therapy. By 12 months of immunomodulator monotherapy, a 45.1% relative reduction was noted. Twelve months of anti–TNF-a monotherapy was associated with a 78.5% relative reduction, and only 9 months of dual therapy was needed to achieve a comparable relative reduction in hospitalization (73.1%). Results suggested that if dual therapy had been initiated earlier, perhaps a greater response in the outcome may have been observed.
Surgical Rates In the first year after index diagnosis and initiation of prescription strategy, 276 IBD-related surgeries occurred. The comparable 1-year surgical rates for each prescription strategy are shown in Figure 3. Anti-TNF monotherapy for 7 months and dual therapy for 5 months were most effective in reducing the probability of IBD-related surgery by 50%. Table 2 highlights the relative reduction in surgery, although power is limited because of the infrequent number of IBD-related procedures performed during the period of observation. After 12 months of immunomodulator monotherapy, a 35.9% relative reduction in surgery was noted, and a 98.3% relative reduction in surgical risk was associated with anti–TNF-a. Only 9 months of dual therapy were required to achieve a similar reduction in RR, suggesting a greater response may have been observed with earlier initiation of dual therapy. All models (hospitalization and surgical rates) were adjusted for diagnosis (UC or CD), smoking status, race/ethnicity, prescription channeling, and pharmacologic effect modifiers (steroids, mesalamine products, NSAIDs, aspirin, cyclosporine, antibiotics, and oral contraceptives).
Discussion A 50% relative reduction in hospitalization was associated with 9.2 months of immunomodulator monotherapy and 8 months of anti–TNF-a therapy, but only 7.7 months of dual therapy were needed for a similar benefit. The probability of an IBD-related surgery in the first year after IBD diagnosis was most influenced by anti–TNF-a therapy with infliximab. Monotherapy for 7 months was associated with a 50% relative
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Figure 3. Surgical rates.
reduction in surgical rates, whereas only 5 months of dual therapy were required to result in the same gains in effectiveness. The dose-response data (Table 2) implied greater benefit if dual therapy was initiated earlier. Veterans who received anti–TNF-a therapy for treatment of IBD were prescribed primarily infliximab, because this was the available biologic at most VA Medical Centers during the period of observation. Early introduction of anti–TNF-a has been shown to improve outcomes when compared with a traditional step-up approach.28 Post hoc data from the CHARM trial29 reveal early treatment with biologic therapy improves treatment response, and the SONIC trial reveals superiority of infliximab over azathioprine in ensuring corticosteroid-free clinical remission and mucosal healing.30 A systematic review suggests earlier use of infliximab improves steroid-free remission and mucosal healing and results in fewer hospitalizations and surgeries, and that benefits increase with earlier initiation of therapy.31 Adherence with infliximab therapy during the first year of CD treatment is correlated with a shorter hospital length of stay and lower inpatient costs than nonadherence,32 and Sprakes et al33 were able to show cost savings in all areas of patient care including total, inpatient and outpatient, surgical, and radiology costs during a 12-month period. This current study lends even more support to post-marketing experience. From a large, stable population, earlier use of infliximab is associated with decreased health care utilization in IBD patients, as measured by objective outcomes. Concerns about safety and cost of earlier use of anti–TNF-a therapies have resulted in limited acceptance of an aggressive approach.34 However, 5-year outcome data of infliximab use have failed to demonstrate increased risk of mortality, and although increased risk of infection was observed, the presence of severe disease and use of prednisone or narcotics carried higher risks.35 In addition, Siegel et al36 demonstrated the benefits of dual therapy would outweigh the risks unless serious infection occurred in 20% of the population and lymphoma in 3.9%, which are 5-fold and 65-fold higher rates than base-case estimates, respectively. Our findings are biologically plausible. Key underlying mechanisms in IBD pathogenesis include damage incurred by proinflammatory cytokines quickly attenuated in vivo after infusion with infliximab. A rapid response to active inflammation leads to improved clinical outcomes within weeks to
months, as noted in this study. Use of antimetabolites may take upward of 6 months to take effect, thus explaining the observed delay in improved outcomes, as seen here. Some limitations to our study must be viewed in context. First, our cohort consisted predominantly of white men, which is in keeping with a veteran population. Results may not be generalizable to women or other ethnic populations. Second, patients were older (mean age, 60.9 years [standard deviation, 14.5]), and age may have influenced prescription, favoring conservative step-up over aggressive top-down therapy. We note the tendency of VA providers who initiated other therapies in 65.8% during the first year after disease diagnosis. Our cohort reflects a time-dependent shift toward older ages in the national VA IBD population.37 Our data add new information to the experience in older IBD patients. It is estimated that 10%–30% of the IBD population is older than the age of 60, and that previous literature suggests the disease course is essentially the same as in the younger population.38 It is novel that we have demonstrated decreased hospitalization and surgery with infliximab. Of the 10.6% prescribed a strategy of interest, most (82%) were prescribed immunomodulator monotherapy. Because of the paucity of prescribed dual therapy (8.5%), the dose-response data are even more impressive and suggest that if dual therapy had been initiated earlier, greater benefit may have been observed. As with any study that uses prescription fill data as the source of exposure, we cannot assess actual use of the drug. However, this is a limitation of any such observational study and is not unique to our study. We also acknowledge that some patients with IBD may never be hospitalized or require an IBDrelated surgery. Thus, our results are likely generalizable to the subset of patients with moderate to severe disease. We did not consider outpatient encounters an outcome, because many veterans use VA clinics only to obtain medications. To guard against measurement bias, we limited our cohort to regular VA users to ensure patients were likely receiving their care at a VA facility. There may be some residual systematic misclassification bias in the assessment of outcomes among veterans 65 years of age who are Medicare eligible.39 Co-utilization of VA and Medicare services has been well documented.39,40 However, our work suggests that veterans who obtain expensive medications (ie, infliximab) tend to stay within the VA system where they are hospitalized and have their surgical procedures.23,37 The limited number of surgical patients
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may affect the precision of our estimates in certain strata; however, the clear statistical significance associated with TNF-a is reassuring, despite limited power, and suggests that the potential benefit is clinically relevant. Our study has several strengths. We collected detailed and complete longitudinal data on a large national cohort in a single-payer system with more than 4 million beneficiaries. The use of a validated algorithm for case ascertainment and outcomes of interest supports the methodological rigor.23,37 The size of the cohort, frequency of events, and ability to assess daily risk given prescription exposure help answer important questions regarding the benefit of infliximab and its impact on hospitalization and surgical rates. Because CD and UC are chronic diseases that must be managed during a lifetime, costs can be substantial.41,42 Because much of this cost is attributable to hospitalizations and surgery, data such as these demonstrating important decreases in hospitalization and surgery within just 1 year provide evidence for the cost savings offered by infliximab, especially in an older population. The delivery of quality health care includes incorporation of data such as these that show earlier adoption of specific classes of therapies leads to improved outcomes in a relatively short time.
Conclusions A 50% relative reduction in hospitalization is observed with 9.2 months of immunomodulator monotherapy, 8 months of infliximab monotherapy, or 7.7 months of dual therapy. A comparable 50% relative reduction in surgery is observed with 7 months of infliximab monotherapy and 5 months of dual therapy. Dose-response data suggest potentially greater benefit if dual therapy is initiated early in the first year after IBD diagnosis. Long-term maintenance of benefit requires further study, as do health-resource implications associated with adverse drug events. References 1. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007;132: 52–65. 2. Colombel JF, Schwartz DA, Sandborn WJ, et al. Adalimumab for the treatment of fistulas in patients with Crohn’s disease. Gut 2009; 58:940–948. 3. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541–1549. 4. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006;130:323–333. 5. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353:2462–2476. 6. Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn’s disease. Gastrointest Endosc 2006;63:433–442. 7. Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 2007;357: 228–238. 8. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004; 350:876–885.
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9. Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med 2007;357:239–250. 10. Lichtenstein GR, Hanauer SB, Sandborn WJ, et al. Management of Crohn’s disease in adults. Am J Gastroenterol 2009;104: 465–483. 11. Lichtenstein GR, Abreu MT, Cohen R, et al. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130:940–987. 12. Travis SP, Stange EF, Lemann M, et al. European evidence based consensus on the diagnosis and management of Crohn’s disease: current management. Gut 2006;55(Suppl 1):i16–i35. 13. Kornbluth A, Sachar DB, Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2010; 105:501–523. 14. D’Haens GR, Panaccione R, Higgins PD, et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn’s and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol 2011;106:199–212. 15. Lichtenstein GR, Yan S, Bala M, et al. Remission in patients with Crohn’s disease is associated with improvement in employment and quality of life and a decrease in hospitalizations and surgeries. Am J Gastroenterol 2004;99:91–96. 16. Lichtenstein GR, Bala M, Han C, et al. Infliximab improves quality of life in patients with Crohn’s disease. Inflamm Bowel Dis 2002; 8:237–243. 17. Baert F, Moortgat L, Van Assche G, et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn’s disease. Gastroenterology 2010;138:463–468. 18. Froslie KF, Jahnsen J, Moum BA, et al. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007;133:412–422. 19. Ford AC, Sandborn WJ, Khan KJ, et al. Efficacy of biological therapies in inflammatory bowel disease: systematic review and metaanalysis. Am J Gastroenterol 2011;106:644–659, quiz. 20. Meier J, Sturm A. Concomitant use of immunomodulators with antiTNF in Crohn’s disease: yes or no? Curr Drug Targets 2010; 11:176–178. 21. Abraham NS, El-Serag HB, Johnson ML, et al. National adherence to evidence-based guidelines for the prescription of nonsteroidal antiinflammatory drugs. Gastroenterology 2005;129:1171–1178. 22. Thirumurthi S, Desilva R, Castillo DL, et al. Identification of Helicobacter pylori infected patients, using administrative data. Aliment Pharmacol Ther 2008;28:1309–1316. 23. Thirumurthi S, Chowdhury R, Richardson P, et al. Validation of ICD9-CM diagnostic codes for inflammatory bowel disease among veterans. Dig Dis Sci 2010;55:2592–2598. 24. Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med 1997;127(Pt 2):757–763. 25. D’Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 1998;17:2265–2281. 26. Newgard CD, Hedges JR, Arthur M, et al. Advanced statistics: the propensity score—a method for estimating treatment effect in observational research. Acad Emerg Med 2004;11:953–961. 27. Harrell FE. Regression model strategies. New York: Springer, 2001. 28. van der Woude CJ, Hommes DW. Are we ready for top-down therapy for inflammatory bowel diseases: pro. Expert Rev Gastroenterol Hepatol 2007;1:243–248. 29. Schreiber S, Reinisch W, Colombel JF, et al. Subgroup analysis of the placebo-controlled CHARM trial: increased remission rates through 3 years for adalimumab-treated patients with early Crohn’s disease. J Crohns Colitis 2013;7:213–221.
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30. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010;362:1383–1395. 31. Feagan BG, Lemann M, Befrits R, et al. Recommendations for the treatment of Crohn’s disease with tumor necrosis factor antagonists: an expert consensus report. Inflamm Bowel Dis 2012;18:152–160. 32. Carter CT, Waters HC, Smith DB. Impact of infliximab adherence on Crohn’s disease-related healthcare utilization and inpatient costs. Adv Ther 2011;28:671–683. 33. Sprakes MB, Ford AC, Suares NC, et al. Costs of care for Crohn’s disease following the introduction of infliximab: a single-centre UK experience. Aliment Pharmacol Ther 2010;32:1357–1363. 34. Rubin DT, Uluscu O, Sederman R. Response to biologic therapy in Crohn’s disease is improved with early treatment: an analysis of health claims data. Inflamm Bowel Dis 2012;18:2225–2231. 35. Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT Registry. Am J Gastroenterol 2012;107: 1409–1422. 36. Siegel CA, Finlayson SR, Sands BE, et al. Adverse events do not outweigh benefits of combination therapy for Crohn’s disease in a decision analytic model. Clin Gastroenterol Hepatol 2012;10:46–51. 37. Sonnenberg A, Richardson PA, Abraham NS. Hospitalizations for inflammatory bowel disease among US military veterans 19752006. Dig Dis Sci 2009;54:1740–1745. 38. Piront P, Louis E, Latour P, et al. Epidemiology of inflammatory bowel diseases in the elderly in the province of Liege. Gastroenterol Clin Biol 2002;26:157–161. 39. Fleming C, Fisher ES, Chang CH, et al. Studying outcomes and hospital utilization in the elderly: the advantages of a merged data
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base for Medicare and Veterans Affairs hospitals. Med Care 1992; 30:377–391. 40. Passman LJ, Garcia RE, Campbell L, et al. Elderly veterans receiving care at a Veterans Affairs Medical Center while enrolled in Medicare-financed HMOs: is the taxpayer paying twice? J Gen Intern Med 1997;12:247–249. 41. Cohen RD, Yu AP, Wu EQ, et al. Systematic review: the costs of ulcerative colitis in Western countries. Aliment Pharmacol Ther 2010;31:693–707. 42. Cohen RD, Larson LR, Roth JM, et al. The cost of hospitalization in Crohn’s disease. Am J Gastroenterol 2000;95:524–530.
Reprint requests Address requests for reprints to: Neena S. Abraham, MD, MSCE, AGAF, FACG, FASGE, Division of Gastroenterology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, Arizona 85259. e-mail: abraham. [email protected]. Acknowledgments This work was accomplished by using the facilities and resources of the Michael E. DeBakey VA Medical Center Health Services Research and Development Center of Excellence (HFP90-020). The authors thank Ms Sonora Hudson for assistance with manuscript preparation. Conflicts of interest The authors disclose no conflicts. Funding Supported by an investigator-initiated grant from Janssen Biotech, Inc.
Dual Therapy With Infliximab and Immunomodulator Reduces One-Year Rates of Hospitalization and Surgery Among Veterans With Inflammatory Bowel Disease NEENA S. ABRAHAM,*,‡ PETER RICHARDSON,‡ DIANA CASTILLO,‡ and SUNANDA V. KANE§ *Section of Digestive Diseases, Division of Gastroenterology and Hepatology, and ‡Houston VA Health Services Research and Development Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, Houston, Texas; and §Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, Minnesota
BACKGROUND & AIMS: Effectiveness of early treatment with biologics and immunomodulator therapy on healthcare utilization remains poorly defined. We assessed rates of hospitalization and surgery within 1 year after initiation of infliximab and/or immunomodulator therapy in a United States cohort of patients with inflammatory bowel disease.
METHODS:
We conducted a retrospective, observational cohort study of veterans with Crohn’s disease or ulcerative colitis by using administrative data from 176 Department of Veteran Affairs facilities (October 1, 2001 through September 30, 2009). Inpatient, outpatient, and death records were linked longitudinally with prescription fill data. Each person-day of follow-up was assessed for treatment with infliximab, immunomodulators, both (dual therapy), or neither. We calculated drug exposure time and used Poisson and logistic regression analyses to assess outcomes.
RESULTS:
The cohort of 20,474 patients included 8042 patients with Crohn’s disease and 12,432 with ulcerative colitis (93.9% male; 72.5% white; mean age, 60.9 – 14.5 years) prescribed infliximab (0.17%), immunomodulator (1.3%), or dual therapy (1.5%). Adjusted models revealed 50% relative reductions in hospitalization among patients who received 9.2 months of immunomodulator monotherapy, 8 months of infliximab, or 7.7 months of dual therapy. A 50% relative reduction in surgery was observed among patients receiving 7 months of infliximab or 5 months of dual therapy. Analysis of dose-response data revealed 73.1% and 92% reductions in risk of hospitalization and surgery, respectively, after 9 months of dual therapy.
CONCLUSIONS:
On the basis of a retrospective cohort study, dual therapy with infliximab and an immunomodulator for <8 months is associated with significant reductions in hospitalization and surgery within 1 year of the start of therapy. These findings indicate that patients with IBD are more likely to benefit if dual therapy is initiated earlier in their first year of therapy.
Keywords: Remicade; Imuran; Anti-Tumor Necrosis Factor (TNF)-a; Patient Management; Therapeutic Strategy.
B
iological therapies are effective in the treatment of active inflammation associated with Crohn’s disease (CD) (infliximab, adalimumab, certolizumab pegol) and ulcerative colitis (UC) (infliximab, adalimumab).1–9 Infliximab has the most extensive published clinical trial data and clinical experience. Its use is a therapeutic recommendation for moderately to severely active CD in the guidelines of the American College of Gastroenterology,10 American Gastroenterological Association,11 and the European Crohn’s and Colitis Organization12 and for moderately to severely active UC in the guidelines of the American College of Gastroenterology.13 Infliximab improves remission rates and quality of life, while reducing rates of surgery and hospitalization.14 Maintenance with infliximab was superior to placebo at week 54 (remission 14% on placebo, 28% at 5 mg/kg, 38% at 10 mg/kg; P < .05).3 Patients on scheduled maintenance therapy had greater mucosal healing,6 fewer hospitalizations and surgery,15 and improved quality of life.16 Among a subset of patients, mucosal
healing supported a sustained clinical remission leading to reduced need for surgery.6,17,18 Meta-analysis confirms that biological therapies targeting tumor necrosis factor (TNF)-a, such as infliximab, are superior to placebo in inducing remission of luminal CD (relative risk [RR], 0.87; 0.80–0.94), with a number needed to treat of eight,19 and of UC (RR, 0.72; 0.57–0.91), with a number needed to treat of four.19 Despite their clear therapeutic benefit, <15% of patients with inflammatory bowel disease (IBD) receive anti-TNF Abbreviations used in this paper: CD, Crohn’s disease; CI, confidence interval; IBD, inflammatory bowel disease; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; NSAID, nonsteroidal anti-inflammatory drug; RR, relative risk; TNF, tumor necrosis factor; UC, ulcerative colitis; VA, Veterans Affairs. © 2013 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2013.06.004
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monotherapy,14 and 40% of patients with active CD receive antiTNF agents in combination with immunomodulator agents (thiopurines or methotrexate).20 It is not known how long immunomodulator monotherapy, biologic monotherapy, or combination therapy must be used to impact hospitalization and surgical rates. Our aim was to ascertain clinical effectiveness, defined as 1-year hospitalization and IBD-related surgical rates, in a national cohort of IBD patients (CD and UC) associated with 3 strategies: (1) immunomodulator monotherapy, (2) anti–TNF-a biologic monotherapy (ie, infliximab), and (3) immunomodulator and anti–TNF-a dual therapy. We hypothesized that infliximab (monotherapy or dual therapy) would result in greater reduction in hospitalization and IBD-related surgery than the other strategies of interest.
Methods Study Design and Data Sources We conducted a retrospective, observational, cohort study of veterans (October 1, 2001–September 30, 2009) by using administrative data from 176 Department of Veteran Affairs (VA) facilities in the United States. The Baylor College of Medicine Institutional Review Board, Houston, TX, approved the research protocol. Patient prescriptions were identified from DSS National Data Extracts accessed from the Austin Automation Center, providing key prescription fill data elements, including facility, dates of fill, days’ supply, and total quantity of drug dispensed. VA administrative data were obtained from the National Patient Care Database, including the Patient Treatment File and the Outpatient Clinic File. The Patient Treatment File record contains patient demographic and hospital discharge information by using procedure codes (Current Procedural Technology and International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] diagnostic codes). The Outpatient Clinic File contains ambulatory patient demographic data, Current Procedural Technology codes, and ICD-9-CM codes. The VA Vital Status File captures deaths reported by the Beneficiary Identification and Record Locator Subsystem, Medicare Vital Status file, and the Social Security Administration. Standard algorithms were used to link administrative to pharmacy fill data to create a longitudinal inpatient, outpatient, and pharmacy refill record for each veteran in the cohort as previously published.21,22
Study Population Veterans aged 18–99 years with IBD were identified by ICD-9-CM codes by using a previously validated algorithm23 with an 88% positive predictive value, 92% sensitivity, and 99% specificity for identification of veterans with CD and an 82% positive predictive value, 84% sensitivity, and 99% specificity for
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identification of veterans with UC. Eligibility criteria included prior inpatient or outpatient VA encounter in the 365 days preceding index diagnosis (to ensure continuous VA enrollment) and no evidence of death 10 days after index prescription of a strategy of interest. Patients were assigned to the CD subcohort if ICD-9-CM codes 550.0–555.9 occurred in the absence of codes for UC (ICD-D-CM codes 556–556.9). Patients not fitting the diagnostic algorithm were excluded from analysis, as were patients with both code categories (defined as indeterminate) to decrease zero cells and improve statistical significance.
Prescription Exposure Each person-day of each cohort member’s longitudinal record was assessed for anti–TNF-a monotherapy (ie, infliximab), immunomodulator monotherapy (ie, azathioprine, mercaptopurine, or methotrexate), overlapping anti–TNF-a and immunomodulator therapy (ie, dual therapy), or absence of therapy (none), as depicted in Figure 1. Dual therapy required a minimum of 7 days of overlapping prescription fill data. Prescription fill data were assessed on a day-by-day basis, whereby an individual exposure period started at t0 and ended with termination of days’ supply or 60-day gaps in fill dates, by using our previously described methodology.21 Exposure to all IBD treatment strategies of interest and other pharmacologic risk factors was considered in a time-varying pattern, assessed daily from pharmacy fill records for each cohort member. Thus, a unique record was created for each time interval for each distinct pattern of prescription fill data per patient. For each strategy prescribed, the aggregate time spent on that regimen by each cohort member in the 365 days after index IBD diagnosis was calculated and expressed in months.
Outcomes of Interest, Potential Risk Factors, and Confounding Variables The outcomes of interest were 1-year hospitalization and 1-year IBD-associated surgical rates. Potential confounding variables considered included demographic features, Charlson–Deyo comorbidity index, and smoking status. Potential modifiers of risk measured included prior IBD-related surgeries and concomitant use of steroids; mesalamine products; nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin; cyclosporine; antibiotics; and oral contraceptives. To address prescription channeling, a propensity score24 was calculated to estimate conditional probability of receipt of each drug regimen. Propensities were analyzed as multinomial conditional probability values24 derived from a polytomous logistic regression model of predictor variables,25 chosen by biological and clinical plausibility and statistical significance (P < .1). This analysis identified potential prescription
Figure 1. Prescription exposure.
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channeling for anti–TNF-a associated with pre-IBD diagnosis prescription of fluoroquinolone antibiotics, steroid use, and immunomodulator therapy and IBD diagnosis (CD vs UC) (data not shown), and this propensity score was included in multivariable models. To adjust for bias when estimating treatment effects,26 we examined the outcome model with and without the propensity score and assessed for significance on each outcome of interest. Models for hospitalization and surgery rates did not differ significantly with inclusion of the propensity for anti–TNF-a; thus, we omitted the propensity score from final models. We also examined for potential interaction between dichotomous predictor variables and their effect on outcomes.
Analytic Methods The c2 test and analysis of variance tested for differences in demographic and clinical characteristics among subgroups. Counts of hospitalizations were modeled by Poisson regression with the drug therapy duration variables as predictors, 1 for each drug regimen of interest. To allow for nonlinearity due to varying per-duration-unit response over different drug-regimen duration ranges, duration responses were rendered as piecewise, continuous linear splines.27 Testing for interactions showed no evidence of departures from the additivity of duration responses to the 3 regimens. Surgical-event rates were modeled in a similar way, but because of low average counts, logistic regression was chosen because of its greater robustness to the effects of outliers and a large number of zero counts associated with small sample sizes of events. Model specifications
took the form: I: Y ¼ b0 þ bIMIM þ bTMTM þ bDD þ other covariates (by exposure to 3 drug therapies), where IM ¼ time on immunomodulator monotherapy, TM ¼ time on anti–TNFa monotherapy, and D ¼ time on dual therapy.
Results The cohort included 20,474 veterans (93.9% male; 72.5% white; mean age, 60.9 years [standard deviation, 14.5]), of whom 8042 had CD and 12,432 had UC (Table 1). There was an equal distribution of Charlson–Deyo comorbidity index scores of 0 vs 1. CD patients had a higher prevalence of surgery preceding 5 years before index diagnosis as well as tobacco use. UC patients were more likely to be prescribed mesalamine products (22.8%). NSAID/aspirin use was prevalent in both disease types. Steroids were prescribed in 14%, and antibiotic use was seen in 30% of subjects. Oral contraceptive use was minimal, as would be expected in a predominantly male cohort. At baseline, 65.8% of patients were on other therapies, including mesalamine monotherapy, antibiotics, steroids, antimetabolite, or cyclosporine only; 23.6% were on no therapy; and 10.6% were prescribed 1 of the prescription strategies of interest; immunomodulator monotherapy was most prevalent (82%), anti–TNF-a monotherapy was prescribed in 8.0%, and dual therapy was prescribed in 8.5%. Among patients receiving infliximab, 62.9% had evidence of induction therapy preceding a maintenance regimen. There was no meaningful difference in prevalence of induction therapy between disease types (61.9% in CD and 65.7% in UC).
Table 1. Baseline Characteristics Characteristic Baseline characteristics Average age (standard deviation) (y) <35 35–65 65 Male Race White Black Other/unknown Comorbidity Charlson–Deyo 0 Charlson–Deyo 1 Charlson–Deyo 2 Charlson–Deyo 3þ Covariate characteristics Surgery 1 y before diagnosis 5 y before diagnosis Tobacco use 1 y before diagnosis 5 y before diagnosis Antimetabolite Steroids Mesalamine NSAIDs Cyclosporine Antibiotics Oral contraceptives
All (N ¼ 20,474)
CD (n ¼ 8,042)
UC (n ¼ 12,432)
P value
60.9 1237 10,932 8305 19,230
58.8 636 4572 2834 7452
62.2 601 6360 5471 11,778
(14.1) (4.83%) (51.16%) (44.01%) (94.74%)
<.0001 <.0001 <.0001 <.0001 <.0001
(14.5) (6.04%) (53.39%) (40.56%) (93.92%)
(14.9) (7.91%) (56.85%) (35.24%) (92.66%)
14,846 (72.51%) 1955 (9.55%) 3673 (17.9%)
5900 (73.36%) 803 (9.99%) 1339 (16.7%)
8946 (71.96%) 1152 (9.27%) 2334 (18.8%)
<.0001 <.0001 <.0001
11,035 4535 2197 2707
4606 1742 814 880
6429 2793 1383 1827
<.0001 <.0001 <.0001 <.0001
(53.90%) (22.15%) (10.73%) (13.22%)
294 (1.44%) 382 (1.87%) 1836 3018 137 2875 4220 7904 42 5883 209
(8.97%) (14.74%) (0.67%) (14.04%) (20.61%) (38.61%) (0.21%) (28.73%) (1.02%)
(57.27%) (21.66%) (10.12%) (10.94%)
131 (1.63%) 172 (2.14%) 833 1313 65 1112 1386 3016 11 2327 77
(10.36%) (16.33%) (0.81%) (13.83%) (17.23%) (37.50%) (0.14%) (28.94%) (0.96%)
(51.71%) (22.47%) (11.12%) (14.70%)
163 (1.31%) 210 (1.69%) 1003 1705 72 1763 2834 4888 31 3556 132
(8.07%) (13.71%) (0.58%) (14.18%) (22.80%) (39.32%) (0.25%) (28.60%) (1.06%)
.0619 .0202 <.0001 <.0001 .0496 .4768 <.0001 .0092 .0821 .6082 .4684
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Figure 2. Hospitalization rates.
Hospitalization Rates One-year hospitalization rates are shown for each prescription strategy in Figure 2, where we demonstrate the time to result in a 50% reduction in hospitalization rate. A 50% reduction in hospitalization rate can be observed after 9.2 months of immunomodulator therapy (P < .0001), after 8 months of anti–TNF-a monotherapy (P < .0001), and with 7.7 months of dual therapy (P ¼ .02). All models were adjusted for diagnosis (UC or CD), smoking status, race/ethnicity, prescription channeling, and pharmacologic effect modifiers (steroids, mesalamine products, NSAIDs, aspirin, cyclosporine, antibiotics, and oral contraceptives). Dose response was calculated to estimate the effect of prescription strategy on hospitalization (Table 2) compared with periods of time with no drug exposure (control). The relative reduction in hospitalization improved as time spent on therapy increased. Model-based relative reduction in hospitalization Table 2. First-Year Hospitalization Rate and Surgical Risk Reductions by Drug Therapy Durations
Duration of therapy Immunomodulator monotherapy 1 month 3 months 6 months 9 months 12 months Anti–TNF-a monotherapy 1 month 3 months 6 months 9 months 12 months Dual therapy 1 month 3 months 6 months 9 months
Relative rate reduction in hospitalizations (compared with no drug exposure) (%)
RR reduction in surgery (compared with no drug exposure) (%)
4.9 13.9 25.9 36.2 45.1
3.6 10.5 20.0 28.4 35.9
1.3 3.9 37.9 67.1 82.6
0.1 0.4 44.2 90.2 98.3
0.7 2.1 4.1 86.1
24.4 56.8 81.4 92.0
rates after 9 months of immunomodulator was 36.2% (95% confidence interval [CI], 24.5%–46.2%); after 9 months of anti–TNF-a monotherapy it was 67.1% (95% CI, 45.6%–80.1%) and 86.1% (95% CI, 55.4%–95.7%) for dual therapy. By 12 months of immunomodulator monotherapy, a 45.1% relative reduction was noted. Twelve months of anti–TNF-a monotherapy was associated with a 78.5% relative reduction, and only 9 months of dual therapy was needed to achieve a comparable relative reduction in hospitalization (73.1%). Results suggested that if dual therapy had been initiated earlier, perhaps a greater response in the outcome may have been observed.
Surgical Rates In the first year after index diagnosis and initiation of prescription strategy, 276 IBD-related surgeries occurred. The comparable 1-year surgical rates for each prescription strategy are shown in Figure 3. Anti-TNF monotherapy for 7 months and dual therapy for 5 months were most effective in reducing the probability of IBD-related surgery by 50%. Table 2 highlights the relative reduction in surgery, although power is limited because of the infrequent number of IBD-related procedures performed during the period of observation. After 12 months of immunomodulator monotherapy, a 35.9% relative reduction in surgery was noted, and a 98.3% relative reduction in surgical risk was associated with anti–TNF-a. Only 9 months of dual therapy were required to achieve a similar reduction in RR, suggesting a greater response may have been observed with earlier initiation of dual therapy. All models (hospitalization and surgical rates) were adjusted for diagnosis (UC or CD), smoking status, race/ethnicity, prescription channeling, and pharmacologic effect modifiers (steroids, mesalamine products, NSAIDs, aspirin, cyclosporine, antibiotics, and oral contraceptives).
Discussion A 50% relative reduction in hospitalization was associated with 9.2 months of immunomodulator monotherapy and 8 months of anti–TNF-a therapy, but only 7.7 months of dual therapy were needed for a similar benefit. The probability of an IBD-related surgery in the first year after IBD diagnosis was most influenced by anti–TNF-a therapy with infliximab. Monotherapy for 7 months was associated with a 50% relative
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Figure 3. Surgical rates.
reduction in surgical rates, whereas only 5 months of dual therapy were required to result in the same gains in effectiveness. The dose-response data (Table 2) implied greater benefit if dual therapy was initiated earlier. Veterans who received anti–TNF-a therapy for treatment of IBD were prescribed primarily infliximab, because this was the available biologic at most VA Medical Centers during the period of observation. Early introduction of anti–TNF-a has been shown to improve outcomes when compared with a traditional step-up approach.28 Post hoc data from the CHARM trial29 reveal early treatment with biologic therapy improves treatment response, and the SONIC trial reveals superiority of infliximab over azathioprine in ensuring corticosteroid-free clinical remission and mucosal healing.30 A systematic review suggests earlier use of infliximab improves steroid-free remission and mucosal healing and results in fewer hospitalizations and surgeries, and that benefits increase with earlier initiation of therapy.31 Adherence with infliximab therapy during the first year of CD treatment is correlated with a shorter hospital length of stay and lower inpatient costs than nonadherence,32 and Sprakes et al33 were able to show cost savings in all areas of patient care including total, inpatient and outpatient, surgical, and radiology costs during a 12-month period. This current study lends even more support to post-marketing experience. From a large, stable population, earlier use of infliximab is associated with decreased health care utilization in IBD patients, as measured by objective outcomes. Concerns about safety and cost of earlier use of anti–TNF-a therapies have resulted in limited acceptance of an aggressive approach.34 However, 5-year outcome data of infliximab use have failed to demonstrate increased risk of mortality, and although increased risk of infection was observed, the presence of severe disease and use of prednisone or narcotics carried higher risks.35 In addition, Siegel et al36 demonstrated the benefits of dual therapy would outweigh the risks unless serious infection occurred in 20% of the population and lymphoma in 3.9%, which are 5-fold and 65-fold higher rates than base-case estimates, respectively. Our findings are biologically plausible. Key underlying mechanisms in IBD pathogenesis include damage incurred by proinflammatory cytokines quickly attenuated in vivo after infusion with infliximab. A rapid response to active inflammation leads to improved clinical outcomes within weeks to
months, as noted in this study. Use of antimetabolites may take upward of 6 months to take effect, thus explaining the observed delay in improved outcomes, as seen here. Some limitations to our study must be viewed in context. First, our cohort consisted predominantly of white men, which is in keeping with a veteran population. Results may not be generalizable to women or other ethnic populations. Second, patients were older (mean age, 60.9 years [standard deviation, 14.5]), and age may have influenced prescription, favoring conservative step-up over aggressive top-down therapy. We note the tendency of VA providers who initiated other therapies in 65.8% during the first year after disease diagnosis. Our cohort reflects a time-dependent shift toward older ages in the national VA IBD population.37 Our data add new information to the experience in older IBD patients. It is estimated that 10%–30% of the IBD population is older than the age of 60, and that previous literature suggests the disease course is essentially the same as in the younger population.38 It is novel that we have demonstrated decreased hospitalization and surgery with infliximab. Of the 10.6% prescribed a strategy of interest, most (82%) were prescribed immunomodulator monotherapy. Because of the paucity of prescribed dual therapy (8.5%), the dose-response data are even more impressive and suggest that if dual therapy had been initiated earlier, greater benefit may have been observed. As with any study that uses prescription fill data as the source of exposure, we cannot assess actual use of the drug. However, this is a limitation of any such observational study and is not unique to our study. We also acknowledge that some patients with IBD may never be hospitalized or require an IBDrelated surgery. Thus, our results are likely generalizable to the subset of patients with moderate to severe disease. We did not consider outpatient encounters an outcome, because many veterans use VA clinics only to obtain medications. To guard against measurement bias, we limited our cohort to regular VA users to ensure patients were likely receiving their care at a VA facility. There may be some residual systematic misclassification bias in the assessment of outcomes among veterans 65 years of age who are Medicare eligible.39 Co-utilization of VA and Medicare services has been well documented.39,40 However, our work suggests that veterans who obtain expensive medications (ie, infliximab) tend to stay within the VA system where they are hospitalized and have their surgical procedures.23,37 The limited number of surgical patients
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may affect the precision of our estimates in certain strata; however, the clear statistical significance associated with TNF-a is reassuring, despite limited power, and suggests that the potential benefit is clinically relevant. Our study has several strengths. We collected detailed and complete longitudinal data on a large national cohort in a single-payer system with more than 4 million beneficiaries. The use of a validated algorithm for case ascertainment and outcomes of interest supports the methodological rigor.23,37 The size of the cohort, frequency of events, and ability to assess daily risk given prescription exposure help answer important questions regarding the benefit of infliximab and its impact on hospitalization and surgical rates. Because CD and UC are chronic diseases that must be managed during a lifetime, costs can be substantial.41,42 Because much of this cost is attributable to hospitalizations and surgery, data such as these demonstrating important decreases in hospitalization and surgery within just 1 year provide evidence for the cost savings offered by infliximab, especially in an older population. The delivery of quality health care includes incorporation of data such as these that show earlier adoption of specific classes of therapies leads to improved outcomes in a relatively short time.
Conclusions A 50% relative reduction in hospitalization is observed with 9.2 months of immunomodulator monotherapy, 8 months of infliximab monotherapy, or 7.7 months of dual therapy. A comparable 50% relative reduction in surgery is observed with 7 months of infliximab monotherapy and 5 months of dual therapy. Dose-response data suggest potentially greater benefit if dual therapy is initiated early in the first year after IBD diagnosis. Long-term maintenance of benefit requires further study, as do health-resource implications associated with adverse drug events. References 1. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007;132: 52–65. 2. Colombel JF, Schwartz DA, Sandborn WJ, et al. Adalimumab for the treatment of fistulas in patients with Crohn’s disease. Gut 2009; 58:940–948. 3. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541–1549. 4. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006;130:323–333. 5. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353:2462–2476. 6. Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn’s disease. Gastrointest Endosc 2006;63:433–442. 7. Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 2007;357: 228–238. 8. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004; 350:876–885.
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Reprint requests Address requests for reprints to: Neena S. Abraham, MD, MSCE, AGAF, FACG, FASGE, Division of Gastroenterology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, Arizona 85259. e-mail: abraham. [email protected]. Acknowledgments This work was accomplished by using the facilities and resources of the Michael E. DeBakey VA Medical Center Health Services Research and Development Center of Excellence (HFP90-020). The authors thank Ms Sonora Hudson for assistance with manuscript preparation. Conflicts of interest The authors disclose no conflicts. Funding Supported by an investigator-initiated grant from Janssen Biotech, Inc.